Use of (thienyl-3)(3-N-morpholine-propy)ketone

ABSTRACT

Furyl, thienyl and thiazolyl compounds of general formula   in in which R is furyl or thienyl linked in the 2 or 3 position or thiazole linked in the 2 position to the indicated carbon atom, X is a divalent aliphatic group having 2 or 3 carbons, Y1 and Y2 together are O or NOH or one is H and the other OH, and Am is an amino group which is a residue of certain amines, and the groups &gt;C Y1 Y2 and Am being linked to the same or different carbon atoms of the group X, their pharmaceutically acceptable acid salts and quaternary ammonium salts have valuable therapeutic properties as neuroleptics, tranquillisers and analgesics.

0 United States Patent 1 [111 3,894,152

Pons et al. July 8, 1975 USE OF (THIENYL-3)(3 N-MORPHOLINE- Primary Examiner Stanley J. Friedman PROPY)KET()NE Attorney, Agent, or FirmStevens, Davis, Miller & [75] Inventors: Andre Lucien Adrien Pons; Max Mosher Fernand Robba, both of Paris; Rene Henri, Espins; Pierre Marcy, Sartrouville, all of France Assignee: lnnothera, Val de Marne, France Filed: Apr. 23, 1973 Appl. No.: 353,362

Related US. Application Data Division of Ser. No. 72,496, Sept.

abandoned.

Foreign Application Priority Data References Cited UNITED STATES PATENTS 6/1965 Huebner 260/239 [57] ABSTRACT Furyl, thienyl and thiazolyl compounds of general formula in in which R is furyl or thienyl linked in the 2 or 3 position or thiazole linked in the 2 position to the indicated carbon atom, X is a divalent aliphatic group having 2 or 3 carbons, Y and Y together are 0 or NOH or one is H and the other OH, and Am is an amino group which is a residue of certain amines, and the groups C Y Y and Am being linked to the same or different carbon atoms of the group X, their pharmaceutically acceptable acid salts and quaternary ammonium salts have valuable therapeutic properties as neuroleptics, tranquillisers and analgesics.

1 Claim, No Drawings USE OF (THIENYL-3)(3-N-MORPHOLINE- PROPY )KETONE This is a division of application Ser. No. 72,496, filed 9/15/70, now abandoned.

This invention relates to new amino derivatives of furane, of thophene and of thiazole, having therapeutic value as neuroleptics, tranquillisers and analgesics, and to compositions containing the same.

According to the present invention there are provided furyl, thienyl and thiazolyl compounds of the general formula wherein R is a furyl or thienyl radical linked in the 2 or 3-position, or a thiazolyl radical linked in the 2- position, to the indicated carbon atom, X is a divalent aliphatic group having 2 or 3 carbon atoms, Y and Y together represent or NOl-l or one of them is hydrogen and the other is hydroxy, and Am represents an amino group which is a residue of a primary or secondary amine selected from propylamine, isopropylamine, butylamine, isobutylamine, secondary butylamine, tertiary butylamine, dimethylamine, diethylamine, dipropylamine, di-isopropylamine, pyrrolidine, piperidine, morpholine and hexamethylene-imine, the groups C Y Y and Am being linked to the same or different carbon atoms of the group X, pharmaceutically acceptable salts of the aforesaid furyl, thienyl and thiazolyl compounds formed with organic or inorganic acids, and pharmaceutically acceptable quarternary ammonium salts of the said furyl, thienyl and thiazolyl compounds.

Suitable acids for the formation of such salts are, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, oxalic, maleic, fumaric, tartaric and citric acids. Suitable quarternary ammonium salts are, for example, the methyl bromide, methyl iodide and benzyl bromide.

The compounds of the foregoing formula may be made by three different methods.

1. by reaction of furyl-lithium, thienyl-lithium or thiazolyl-lithium with the appropriate amino nitrile.

2. by reaction of a primary or secondary amine with a furane, thiophene or thiazole derivative carrying a halogenated ketonic aliphatic substituent.

3. by reaction of an amine and formaldehyde with an acetyl or propionyl furane, thiophene or thiazole by the Mannich reaction.

In the first of these processes it is preferred to work in an anhydrous medium and in an atmosphere of nitrogen, preferably at low temperature. Thus the amino nitrile may be added to the organo-lithium compound and stirred at low temperature for several hours. By hydrolysing and acidifying the pH to 4 to 5 with acetic acid the amino ketone hydrobromide may be isolated. One can convert to the amino ketone by the action of an aqueous solution of sodium carbonate and extraction with an organic solvent, then converting the base to a salt with a mineral or organic acid or converting it to a quarternary ammonium salt.

The organo-lithium compound can be prepared by reaction of an alkyl-lithium with the furane, thiophene or thiazole derivative or by direct metallisation of the heterocyclic compound.

In accordance with the second process the brominated ketonic compound and the primary or secondary amine may be condensed in an alcoholic medium, e.g. in ethanol for example by allowing the reaction mixture to stand at ambient temperature for several hours.

To obtain the brominated ketonic compound, bromine in solution in chloroform or benzene may be reacted with the acyl derivative of furane, thiophene or thiazole. The position of linkage of the halogen on the acyl chain may be determined by nuclear magnetic resonance spectra.

The Mannich reaction may be carried out in the classical manner by warming to reflux for several hours in ethanol, a mixture of the acylated heterocyclic derivative, an amine hydrochloride and paraformaldehyde.

The oximes corresponding to the ketones may be obtained by warming to reflux, in ethanol, at a temperature of C, a mixture of the ketone, hydroxylamine hydrochloride and potassium acid carbonate. The oxime may be isolated either in basic form by cooling the reaction mixture or transformed into a salt of mineral or organic acid.

To prepare the alcohols corresponding to the ketones, the ketonic group may be reduced to a secondary alcohol group, in methanol or ethanol solution, by treatment with sodium or potassium borohydride at ambient temperatures. The amino-alcohol produced is extracted with the aid of an organic solvent and the extract is dried by evaporating the solvent. The product may be converted to a salt by treatment with mineral or organic acid.

The following examples will serve to illustrate the invention. Temperature given are in degrees Centigrade.

EXAMPLE 1 (Thienyl-3) ('y-N-morpholino-propyl) ketone A solution of n-butyl lithium is prepared under nitrogen at 0 to 5, with 2 g of lithium and an anhydrous solution of 23 g of n-butyl bromide in 250 cc of ethyl ether. To this solution, stirred and cooled to 60, is added drop by drop a solution of 14g of 3-bromo thiophene in cc of ethyl ether. Stirring is continued for 1% hours after the addition. There is then added, drop by drop, with stirring, a solution of 10g of 4-N- morpholino butyronitrile in 20 cc ethyl ether while maintaining the temperature at -50. Stirring is effected for 4 hours at 50 and then hydrolysis is effected by a mixture of crushed ice and acetic acid in proportions such that the final pH of the aqueous solution is about 5. The ether is decanted and the precipitate which is formed in the aqueous phase after 24 hours in the ice box is removed. It is separated and dried. White crystals of the monohydrobromide of (thienyl-3)(y-N-morpholino-propyl) ketone are thus obtained in a yield of 70% (m.p.l65).

The compound is crystallisable from absolute ethano].

The hydrochloride of the compound presents itself in the form of white crystals (m.p. crystallisable from absolute ethanol. It is obtained in the following manner: the base is obtained from the hydrobromide by the action of an aqueous alkaline solution, extracted with chloroform, dried over sodium sulphite, evaporated to dryness in vacuo and the residue redissolved in ethyl ether, saturated with anhydrous hydrochloric acid and the precipitate separated.

The mono methyl iodide of the compound presents itself in the form of white crystals (m.p. 181). It crystallises from absolute ethanol. It is prepared from the base in acetone solution by the action, at ambient temperature of a solution of methyl iodide in acetone.

The oxalate of the compound is obtained, in a yield of 90% by heating the base with zalic acid for 15 minutes, in acetone to reflux. It presents itself in the form of white crystals (m.p. 197) and crystallises from methanol. The maleate (m.p. 105) and fumarate (m.p. 125) may be prepared in the same way.

EXAMPLE 2 (Thiazolyl-2)('y-Nhexamethylene-imino-propyl) ketone A solution of n-butyl lithium is prepared from 2.1 g of lithium and 21 g of n-butyl bromide in 100 cc of anhydrous ethyl ether and under nitrogen. It is cooled to 20, 20 g of 2-bromothiazole dissolved in 50 cc of ethyl ether is added and stirring effected from 1 hour at 20. It is cooled to 40 and there is added, with stirring, a solution of 20 g of 4-N-hexamethylene-iminobutyronitrile in 50 cc of ethyl ether. It is stirred for 12 hours and then poured onto 150 g of crushed ice. There is then added cc of acetic acid to bring the pH to 4 and the precipitate is separated. It is dried and recrystallised from acetonitrile. White crystals (m.p. 195) of (thiazolyl-2)('y-N-hexamethylene-imino-propyl) ketone are obtained in a yield of 35%.

EXAMPLE 3 (Furyl-2)(a-tertiary butylamino-ethyl) ketone and its hydrochloride.

a. (Furyl-2)(a-bromo-ethyl) ketone There is added, during an hour at 20, 21 cc of bromine to a stirred solution of 2-propionyl furane in 100 cc of chloroform. Stirring is continued for two hours. The reaction mixture is placed in a decanting vessel and stirred with an aqueous solution of sodium carbonate, and a saturated aqueous solution of sodium chloride. The product is dried over sodium sulphate and distilled in vacuo. (Furyl-2)(a-bromo-ethyl) ketone is obtained, 60 g (yield 74%) in the form of a yellow oil (b.p/2mm 100).

b. (Furyl-2) (a-tertiary-butylaminoethyl) ketone and its hydrochloride A solution of 4 cc of (furyl-2) (a-bromoethyl) ketone and 6 cc of tertiary butylamine in 50 cc of absolute ethanol are allowed to stand for 24 hours at ambient temperature. The product is evaporated to dryness in vacuo, an aqueous solution of sodium carbonate is added to the residue and stirred and the product is extracted with chloroform. It is dried over sodium sulphite and the base obtained is converted to its mono hydrochloride by saturation with anhydrous hydrochloric acid. White crystals are obtained (m.p. 222) with a yield of 70%. The hydrochloride is recrystallised in absolute ethanol.

EXAMPLE 4 (Thienyl-3)(a-isopropylamino-ethyl) ketone a. (Thienyl-3)(a-bromo-ethyl) ketone To a solution of 36 g of 3-propionyl thiophene in 100 cc of anhydrous benzene there is added, with stirring 15 cc of bromine during 1 hour at 20. Stirring is continued for an hour at ambient temperature. The organic phase is washed with water and then with an aqueous solution of sodium carbonate. The solvent is eliminated and the residue distilled in vacuo. (Thienyl-3)(abromo-ethyl)ketone is obtained, 45 g (yield in the form of a yellow oil (b.p. 4mm

b. (Thienyl-3 )(B-isopropylonino-ethyl )ketone A solution of 4 cc of (thienyl-3)(a-bromoethyl) ketone and 6 cc of isopropylamine in 50 cc ethanol is allowed to stand for 24 hours at ambient temperature. After evaporation to dryness in vacuo there is added to the residue an aqueous solution of sodium carbonate and the product is extracted with chloroform. It is dried over sodium sulphate, the solvent removed, the residue re-dissolved in ethyl ether and transformed into its hydrochloride by saturation with anhydrous hydrochloric acid. The hydrochloride is obtained as white crystals (m.p. 225) in a yield of 81%. It is recrystallised from absolute alcohol.

EXAMPLE 5 (Thiazolyl-2 B-dimethylamino-ethyl )ketone A mixture of 3 g of 2-acetyl thiazole, 2 g of dimethylamine hydrochloride, 1 g of paraformaldehyde and 2 drops of ION hydrochloric acid in 30 cc of 96% ethyl alcohol is heated to reflux for 20 hours. It is concentrated to half-volume, cooled and 100 cc acetone is added. After leaving the solution for some hours in an ice-box, the crystals are separated and the product recrystallised from 96% ethyl alcohol. White crystals are obtained (m.p. 203) in a yield of 45%.

EXAMPLE 6 (Thienyl-3)(y-N-morpholino-propyl) ketoxime A solution of 3.20 g of (thienyl-3)(y-N-morpholinopropyl) ketone, 1.40 g of hydroxylamine hydrochloride and 3 g of acid potassium carbonate in ml of 80% ethyl alcohol is heated to reflux for 45 minutes. After cooling, the product obtained is separated and recrystallised from ethyl ether. White crystals (m.p. 122) are obtained in a yield of 70%. The base is converted to the mono hydrochloride by saturation of its solution in ethyl ether with gaseous anhydrous hydrogen chloride. White crystals are obtained (m.p. 179); the hydrochloride crystallises in ethanol.

EXAMPLE 7 (Thieny1-2)(y-isopropylamino-ethyl) carbinol Sodium borohydride, 1.1 g, is added in 15 minutes at 0 to a solution of 5.90 g of (thienyl-2)('y-N- isopropylamino-ethyl) ketone in 30 cc of methanol. After 1 hour stirring at 20 there is added 100 cc of water and the product is extracted with ether. The ether phase is dried over anhydrous sodium sulphate and the solvent then eliminated. The residue is dissolved in 40 cc of anhydrous ethyl ether and saturated with anhydrous hydrochloric acid. The hydrochloride obtained is separated and recrystallised from absolute ethanol. White crystals are obtained (m.p. 201) in a yield of 81%.

EXAMPLE 8 (Thienyl-3)('y-di-isopropylamino-propyl) methanol phase is dried over anhydrous sodium sulphate, the solvent is evaporated and the base obtained is converted to'the hydrochloride. White crystals are obtained (m.p. 146) in a yield of 80%: the hydrochloride crystallises 5 from a mixture of ethanol and ethyl ether.

In Tables 1 to 3 there are set out the compounds prepared according to the foregoing Examples together with other compounds which can be obtained by the processes of preparation described.

TABLE 1 R CO X Am Com- Compound Solvent of Yield pound R X Am nature m.p. recrystal- No. lisatlon 0 CH-- CH 1 NHCH hydrochloride 227 ethanol 95 H CH;

i ethanol 0 CH CH;; plus 2 I l NHCH hydrochloride 201 ethyl 90 CH C H ether -CH CH; 3 I I NHCH CH hydrochloride 203 ethanol 75 CH1! 3 0 CH- Cl-l; o 4 l l NHC EH CH hydrochlorlde 222 ethanol 70 CH; :l s CH cl-h, a 5 I I -NHCH C hydrochlorlde 225 ethanol 80 i l 3 z;

5 CH- CH;, a o l l NHCH hydrochlorlde 210 ethanol 75 CH;; 2 s

5 Cl-l chhl 7 I l l NHCH CH hydrochloride 220 ethanol CH3 CH1:

5 CH- crl 8 i i NHC CH hydrochlorlde 1 85 ethanol 65 CH CH .5 C H 9 (CH N hydrobromide 48 aceto-nltrlle 50 Crllr,

:l -1( 10 (CH N hydrobromlde 98 acetomtrlle C H (i) plfis ethyl et er 5 methyl iodide l70 ethanol 1 1 (Cl-l N l hydrobromide 158 acetonitrile S 12 (CH ).-l- -N h drobromide 165 ethanol l I 2 O y hydrochloride 1 ethanol methyl iodide l8l ethanol 5 hydrobi'omide 2 1 0 ethanol 75 1 3 (CH N U 2 i hydrochloride 198 ethanol I I (CH hydrobromide 223 acetonitrile 60 hydrochloride 210 ethanol 80 5 Y CH l5 ll I (CH -N h droehlorlde 203 96% ethyl- 45 CH;, alcohol l6 l 5 Tr (CH N hydrobromide ethanol 25 17 I 5 T6 (CH- hydrobromide 207 ethanol 25 13 I S Y 2 :l N O hydrochloride 210 ethanol 34 S 19 ll m (CH N hydrobromide ethanol 35 LLBLEZ S C N lj c (CH Am Com- Compound Solvent of Yield lrilound Am Nature m.p. recrystallisation o. v v

H .-i v N gH base 80 ethanol 60 HI crl CH 2| i: base 190 hydrochloride 1 ethanol 80 22 base 1 ethanol hydrochloride 1 70 ethanol 23 base 122 ethyl ether 70 O h drochloride 179 ethanol plus y .J ethyl ether 24 C 11,, base 83 ethyl ether N hydrochloride 135 ethanol plus C 11 ethyl ether 25 hydrochloride 197 ethanol plus ethyl ether 75 TABLE 3 f R CHOH X Am r COMPOUND Com- R X Am Nature m.p. Solvent Yield pound of recryst- No. allisation o :l 26 l l NHCH hydrochloride 148 96% ethyl 65 Ch C l-lr, alcohol 5 CH CH 27 I l NHCH hydrochloride 201 ethanol 80 I CH cli 5 CH l 28 l NHCH CH hydrochloride 175 ethanol 70 l 1 CH i 5 Cl-1 CH 29 I I l NHC CH hydrochloride 205 ethanol 70 CH1 \C S CH CH.1 30 l NHCH hydrochloride 235 ethanol CH c l-l 5 CH CH;, 31 1 l l NHCH hydrochloride 162 ethanol 50 can lh CH- CH; l 32 I 1 I NHCH CH hydrochloride 187 ethanol 80 CH cl-l 5 CH- Ch 33 l l NHCH hydrochloride 171 ethanol. 75

CH;, C 11 a S v 34 El (CH N(C H methiodide ethanol 60 35 5 Hi).-. -N(iC,,l-l,) hydrochloride 146 *ethanol 80 l I plus ethyl ether 36 5 -(CH N hydrochloride 113 ethanol 70 l l plus ethyl ether TABLE 3 Continued R CHOH X Am COMPOUND Com- R X Am Nature m.p. Solvent Yield pound of recryst- No. allisation 37 S -(CH hydrochloride 226 ethanol 70 I l N plus ethyl ether methiodide 1 35 ethanol 38 5 (CH -N O methiodide 157 ethanol 65 I I J base 66 ethyl ether 5 39 (C 2):; -N hydrochloride 228 ethanol 70 I l plus ethyl ether The compounds of the invention have been made the subject of a pharmacological study showing an activity localised at the level of the central nervous system and showing, in particular, the neuroleptic, tranquilising and analgesic properties of the compounds.

l. ACUTE TOXICITY The acute toxicity of a number of the furan, thiophene and thiazole compounds chosen by way of example has been determined by the intraperitoneal route in the mouse. The calculation of the DL 50 has been effected by the method of MILLER and TAINTER (MILLER L. C., TAINTER, M. L. Proc. Soc. EXPTL. BIOL. MED. 1944 -57- 261, 264.)

In the particular case of the hydrobromide of (thienyl-3) (3-N-morpholinopropyl) ketone, the acute toxicity has been evaluated by intravenous, intraperitoneal, subcutaneous and oral routes, in the mouse, by the same method. The different results are presented in the tables which follow.

11. Potentialisation of experimental sleep in the mouse The sedative activity of the furane thiophene and thiazole derivatives has been studied in the mouse by two techniques of potentialisation of experimental sleep induced by barbiturates.

A. Prolongation of experimental sleep Sodium hexobarbital in 0.5% solution in an isotonic sodium chloride solution injected by the intraperitoneal route in the mouse at a dosage of 50 mg/kg, is not hynogenic.

The previous injection of neuroleptic or tranquillising substances leads, in the case of a number of the mice treated, to the appearance of sleep of variable intensity and duration according to the dose of the sedative administered.

The percentage of animals which sleep is noted.

The average duration of the latency time corresponds to the difference between the average time of injection of the sodium hexobarbital (A) and the average time of the loss of recovery reflex (B), thus (B) (A).

The average duration of sleep corresponds to the difference between the average time of loss of recovery reflex (B) and the average time where the mice recover spontaneously (C), thus (C)-(B).

Tests have been effected comparatively with meprobanate, hydroxyzine and chlorpromazine chosen as the reference substances.

The different results obtained with certain derivatives studied by way of example are presented in the tables 8, 9 and 10 which follow, the average duration being calculated on the number of mice put to sleep.

B. Test for re-inducement to sleep Sodium hexobarbital, in 0.8% solution in an isotonic sodium chloride solution, injected intraperitoneally at a dose of mg kg, induces, in the five minutes which follow the injection, the appearance of sleep of duration varying from 15 to 30 minutes in 100% of the animals treated.

On awakening, the injection of neuroleptic or tranquillising substances, induces the re-sleeping of some of the animals. The latency time and the duration of the second period of sleep vary according to the size of the dose administered. The percentage of animals which resleep is noted.

The average duration of the latency time corresponds to the difference between the average time of injecting the products under test, immediately after the first awakening (D) and the average time of the second loss of recovery reflex (E), thus (E)(D).

The average duration of the second sleep period corresponds to the difference between the average time of the second loss of recovery reflex (E) and the average time of the second awakening (F), thus (E)(E).

The tests have been effected comparatively to chlorpromazine chosen as the reference neuroleptic.

The different results obtained with the derivatives studied by way of example are shown in the three tables which follow, the average duration being calculated on the number of mice induced to sleep or re-sleep.

111. Analgesic activity The analgesic activity of the furane, thiophene and triazole compounds has been examined and illustrated in the mouse according to the following two techniques:

A. Technique of the phenyl-paraquinone of $1316- MUND, E.A., CADMUS A., Lu, G. J. Pharmacol Exp. Therapy, 1957, 119, 453.

This study has been effected relative to aminopyridine, as the reference analgesic. The different results obtained with certain compounds studied by way of Example, are presented in Tables 11, 12 and 13.

B. Hot plate test.

Mice placed in a Pyrex glass beaker immersed in a steam bath at 65 lick their fore-paws after 4 to 7 seconds exposure to the temperature. The previous administration of an analgesic substance retards the appearance of the licking reflex.

Morphine and amidopyrine hydrochlorides are used as reference analgesics.

TABLE 9 Prolongation of experimental sleep in the mouse The thiophene derivatives were administered 30 minutes b f the Sodium m n-50 mg/kg i'p' promazine were administered 30 minutes before the sodium hexobarbital (50 mg/kg i.p. 0.5% solution) 0.5% solution) TABLE Prolongation of experimental sleep in the mouse The furan and thiophene derivatives and the chlor- 'com- Doses Route Conc. Percentage Average duration pound in in g/ 100 ml of animals No. mg/kg of put to of latency of sleep solution sleep time 26 30 s c 0.30 20 5 nm 6 run 27 20 s c 0.20 60 7 mn 08 s 10 mn 28 20 s c 0.20 50 4 mn 03 s 17 mn 29 30 s c 0.30 60 4 nm 57 s 8 nm 01 s 30 20 sc 0.20 60 6 mn 35 s 16 nm 31 20 s c 0.20 30 5 mn 20 s 11 nm 32 20 s c 0.20 30 6 nm s 28 mn 33 s c 0.20 40 7 mn 26 s 14 nm 34 15 so 0.15 40 7mn 15s 6mn 37 15 so 0.15 20 5mn 8mn Methiodide 75 v o 0.75 60 8 mn l5 s 17 mn 38 15 se 0.15 80 3mn45s llmn Methiodide 39 30 s c 0.30 60 3 mn s 16 mn Chlorproma- 2 5.0 0.02 100 1 nm 26 s 44 nm YCH Am Com- Doses Route Conc. percentage Average duration pound in in g/lOO ml of animals No. mg/kg of put to. of latency of sleep solution sleep time I 20 s.c. 0.30 80 4 mn 37 s 9 nm 22 s 2] 20 s.c. 0.20 100 2 mn 52 s 36 mn hydrochloride 22 I5 s.c. 0.15 70 5mn 12s 19 mn hydrochlor- 20 s.c. 0.20 80 4 nm 41 s 30 mn ide 75 v.0. 0.75 70 3 10 s 37 mn 23 2O s.c. 0.15 70 6 nm 23 rnn hydrochor- 50 v.0. 0.50 30 3 nm s 14 mn ide 75 v.0. 0.50 50 4 mn s 25 mn 24 20 s.c. 0.20 3 nm 42 s 15 mn hydrochloride 25 20 5.0. 0.20 5 mn 23 s 26 mn chlor- 2 s.c. 0.02 3 nm 35 mn promazine 3 i.p. 0.03 1 nm 40 s 50 mn S lfllOH m C (C H Am Compound Doses in Conc. First sleep, afterinjection of Second sleep after injection of the N04 mg/kg in sodium hexebarbital (80 mg/kg test compound g/lOOml -i.p.)

f solution Percentage Average Duration Percentage Average Duration of animals of latency of sleep of animals of latency of put to time put to time sleep sleep sleep 2] l5 0.l5 100 2m38s mn 100 6mn 09s 27 mn hydrochloride 22 l0 0.10 100 2mn 42s 17 rnn 9O 4mn 05s 22 rnn hydrochloride 23 0.20 90 2 mn 49 s 20 mn 90 3 nm 33 s 29 mn hydrochloride I5 0.15 90 2mn 28s l7mn 9O 5mn 33s 3lmn isotonic 10 solution of ml/kg I00 3 nm 39 s 18 mn O NaCl TABLE 1 1 TABLE 13 Test for re-inducement of slee in the mouse p 20 Test for re-mducement of sleep in the mouse The thiophene and thiazole derivatives and the chlorpromazine and the isotonic NaCl solution were administered subcutaneously immediately after the first awakening.

The thiophene derivatives and the isotonic solution of NaCl were administered subcutaneously immediately after the first awakening Second sleep after injection of the Compound No. Doses in Conc. First sleep, after injection of mg/kg in sodium hexobarbital (80 mg/kg test compound g/l 00ml -i.p.)

of solution Percentage Average Duration Percentage Average Duration of animals of latency of sleep of animals of latency of put to time put to time sleep sleep sleep 27 0.30 100 3 rnn 48 s 14 mn 6O 2 rnn 50 s 8 mn 37 20 0.20 90 5 nm 22 s l9 rnn 30 9 rnn l3 s 18 mn hydrochloride 39 20 0.20 90 3 mn 50 s 27 Inn 30 7 mn l6 s ll mn isotonic 10 100 3 mn 39 s 18 rnn 0 solution of ml/kg NaCl R CO X Am Compound No. Doses Conc. First sleep, after injection of Second sleep after injection of the in mg/ in sodium hexobarbital (80 mg/kg test compound kg g/ 100ml -i.p.)

of solution Percentage Average Duration Percentage Average Duration of animals of animals put to of latency of sleep put to sleep of latency of sleep time time sleep 9 20 0.20 lOO 3mn 41 s 2mn 36s 70 9mn 51 s 22 rnn ll 20 0.20 100 2 rnn 53 s 9 mn 36 s 90 l0 mn 30 rnn l2 5 0.05 100 3 rnn 36 s 29 rnn 5O 8 nm 8 rnn hydrobromide 10 0.10 100 4 nm 26 s 17 mn 9O 4 mn l5 s 17 nm 20 0.10 100 3 mn 52 s 20 mn' 90 2 mn s l9 mn l3 10 0.10 100 3mn 16s 29 nm 4mnl2s 26 rnn hydrochloride l4 l0 0.l0 I00 2mn 57s 32 rnn 60 2mn 50s 26 mn hydrochloride 16 20 0.20 I00 3 rnn 28 5 l5 nm 30 3 rnn 40 5 l5 mn Chlorpromazine 2 0.02 100 5 mn l6 s 20 rnn I00 3 mn l8 s 22 rnn 2 0.02 100 3 nm 02 s 15 mn' 2 rnn 22 s 22 mn isotonic solution 10 of NaCl ml/kg 4 rnn 27 s 23 mn 0 l0 ml/kg I00 2 mn 11 s 16 rnn 0 TABLE 12 TABLE 14 Test for re-inducement of sleep in the mouse 65 Test to phenylparaqumone m the mouse The thiophene and the isotonic solution of NaCl were administered subcutaneously immediately after the first awakening The thiophene, thiazole and furane derivatives, and the amidopyrine were administered subcutaneously 30 minutes before the phenylparaquinone (P.P.Q) (0.2 ml per mouse i.p. 0.02g/l00ml solution) R CO X Am Com- Doses Conc. Percentage of reduction of the number of pound in in S.D.*for each interval of time (t) No. mg/kg g/ 100 ml expressed in minutes (mn) of solution 5 t l 10 t l l 30 0.3 48 72 2 30 0.3 33 66 9 20 0.20 75 67 1 1 20 0.10 97 90 12 0.10 61 55 hydro- 0.15 55 36 bromide 0.25 93 78 13 15 0.15 55 20 hydrochloride 14 I5 0 15 45 32 hydrochloride 16 20 0.20 36 40 Amido- 10 0.10 40 pyrine SD. Syndrome sickness induced by the injection i'ntraperitonealy of phenylparaquinone.

TABLE 15 Test to phenylaraquinone in the mouse The thiophene derivatives and the amidopyrine were 25 administered subcutaneously 30 minutes before the phenylparaquinone (P.P.Q.) (0.25 ml per mouse i.p.

TABLE 17 Heated Plate test, in the mouse The thiophene derivatives, amidopyrine and isotonic solution of NaCl were administered intraperitoneally '30 minutes before exposure of the mouse to the heated 0.02 g/lOO m1) plate.

R CO X Am Compound No. Doses Conc. Average duration of Prolongation of in in g/lOO ml exposure in seconds the average durmg/kg of ation of exposure solution in seconds 9 0.5 13.6 6.7 10 50 0.5 10.2 3.3 hydrobromide ll 50 0.5 22.5 15.6 12 50 0.5 10.6 3.7 hydrobromide 13 50 0.5 18.4 11.5 hydrochloride [4 50 0.5 19.4 12.5 hydrochloride Amidopyrine 1.0 14.2 7.3 isotonic solution of 10 6.9 NaCl ml/kg m: (CH Am SD. Syndrome sickness induced by the injection intraperitone ziiyl Bi Bilfihflparaquinone.

TABLE 16 Test of phenylparaquinone in the mouse The thiophene derivatives and the amidopyrine were administered subcutaneously 30 minutes before the phenylparaquinone (P.P.Q) (0.25 ml per mouse i.p. 0.02 g/lOO ml) TABLE 18 Heated plate test, in the Mouse S OH in. E (CH Am Compound No. Doses Conc. Average duration Prolongation in in g/lOO ml of exposure in of the average mg/kg of seconds duration of solution exposure in seconds 21 hydrochloride 20 0.20 17.3 11.2 22 hydrochloride 20 0.20 1 1.6 5.5 23 hydrochloride 20 0.20 8.5 2.4 24 hydrochloride 20 0.20 8.9 2.8 25 20 0.20 15.6 9.5 morphine hydrochloride 20 0.20 12.5 6.4 isotonic solution of 10 6.1 NaCl ml/kg R Cl-lOH X Am Compound Doses Conc. Percentage of reduction of the number No. in in of SD. for each interval of time (t) mg/kg g/ 100 ml expressed in minutes (mn) of solution 5 t l 0 10 t 15 27 30 0.30 45 72 34 20 0.20 38 45 37 20 0.20 47 62 hydrochloride 37 10 0.10 60 32 methiodide 39 10 0.10 48 29 Amidopy- 10 0. 10 45 rine S.D. Syndrome sickness induced by the injection intraperitonealy of phenylparaquinone.

The new compounds of the invention may be used in Example A Tablets therapy by reason of their neuroleptic, tranquillising y (v- -h'g p -p py 0,200 g analgesic properties for the treatment of functional fi igz 8 (H00 g nerve troubles. In particular they may be administered Magnesium Stearate 0.005 g in the following different nervous and algesic conditions: 50

nervous tension, hyperemotivity, instability psychosis W in ordinary life (anxiety, distress, nervousness, irri- (Thlenym) 10 g bTt ketone hydrobromide l l y Distilled water to make 100 ml ma or functional troubles due to psychic tension:

digestive troubles (spasms, aching), cardiovascular troubles (precardiac pain) and gynecological Example C lnjecwble Solution troubles (pre-menstrual syndromes) Z- PS P -P PY 0-050 1;

$10116 y 1'0 [Grill 6 The new derivatives may be presented for oral, endo- Distilled water to make 5 ml rectal or parenteral administration In man and animals, particularly in association with excipients appropriate to these routes. Thus, for example, they can be presented in the form of tablets, capsules, cachets, drinkable solutions, suppositories or injectable solutions. The invention includes, accordingly, pharmaceutical compositions which comprise one or more of these new derivatives.

The dosage unit may, as required, contain 50 to 500 mg of active substance.

The following pharmaceutical compositions are given by way of example:

UNITED STATES PATENT AND TRADEMARK OFFICE QETIFICATE OF CORRECTEON G PATENT NO. 3,894,152

DATED I July 8, 1975 INVENTOR(S) Andre Lucien Adrien PONS et al It is certified that error appears in the aboveidentified patent and that said Letters Patent s are hereby corrected as shown below:

Ihe names of the third and fourth inventors should be corrected to read:

-Rene Henri Pierre Marcy of Espins G and Denise Jeanne Claude Duval of Satrouville Signed and Scaled this 0 [SEAL] wentieth Day of AprilI976 A ties t:

RUTH C. MASON C. MARSHALL DANN Arresting Officer i I Commissioner njlarenls and Trademarks 

1. A PROCESS FOR THE TREATMENT OF A PATIENT TO INDUCE A NEUROLEPTIC, TRANQUILIZING OR ANALGESIC EFFECT WHICH COMPRISES ADMINISTERING TO THE PATIENT 50 TO 500 MG OF (THIENYL-3) (3N-MORPHOLINO-PROPYL) KETONE AND A PHARMACEUTICALLY ACCEPTABLE DILUENT. 